The problem of fibrosing interstitial lung diseases (ILDs) unites specialists from different areas: pulmonologists, radiologists, therapists, rheumatologists, occupational doctors and others. Actual achievements in studying fibrosing ILDs which are connected with development of immunology and molecular biological methods for the determination of biomarkers, new principles of image-diagnostics of lung pathology, search of new therapeutic “targets”, dictate the necessity of integration of knowledge by specialists from different areas of medicine for improvement pharmacotherapy algorithms. These algorithms directed to decrease fibrosis progression in ILDs, improve quality and increase lifespan of the patients.

Despite the large number of studies devoted to the study of systemic sclerosis (SSc), the high risk of developing lymphomas in this disease, the relationship of their development with certain subtypes of SSc and specific SSc-associated autoantibodies is still debated in the literature. AIM To study demographic, clinical, laboratory and immunological characteristics of patients with a combination of primary Sjogrens syndrome (pSS) and SSc and diagnosed lymphoproliferative diseases (LPDs); to characterize morphological/immunomorphological variants and course of non-Hodgkins lymphomas (NHL), developing in patients with these rheumatic diseases (RDs). MATERIALS AND METHODS In 19982018 at the Nasonova Research Institute of Rheumatology, 13 patients with clinical and laboratory manifestations of pSS (12) and SSc (13) were diagnosed with various lymphoproliferative diseases (LPDs). In 3 cases, an induced RD was observed: 1 case of a diffuse, rapidly progressive form of SSc, 2 cases of pSS in combination with a limited form of SSc after chemotherapy and radiation therapy of Hodgkins lymphoma (1), B-cell NHL (1) and CR of the breast (1) respectively. The first 2 cases were excluded from the analysis, since the development of lymphomas is not pathogenetically associated with RD. RESULTS Of 11 patients with LPDs, 10 after a long course of RDs were diagnosed with NHL [MALT lymphoma of the parotid salivary glands 7, disseminated MALT lymphoma 2, disseminated MALT lymphoma with transformation into diffuse large B-cell lymphoma (DLBCL) 1]. RDs debuted with Raynauds phenomenon (RP) in 64.5% and pSS manifestations in 45.5% of patients. Stomatological manifestations of pSS were characterized by recurrent parotitis in 36%, significant parotid gland enlargement with massive infiltration of labial salivary glands (focus score 4) in 100%, severe xerostomia in 70%, extraglandular manifestations and lymphadenopathy in 50% of patients. The course of the SSc was characterized by mild RP with various types of capillaroscopic changes and mild lung changes and non-significant progression during long-term follow-up (median 22 years). The entire spectrum of SSс specific antibodies (anticentromere antibodies 60%, antibodies to ribonucleoprotease III 30%, Pm/Scl 10%), excepting antibodies to topoisomerase I, as well as pSS specific autoantibodies (antiRo/La 70%, RF (rheumatoid factor) 90%), were detected in patients with a combination of these RDs. CONCLUSION pSS is often combined with a limited form of SSc regardless of the type of autoantibodies detected. The presence of pSS, rather than SSc, is a high-risk factor for the development of NHL in this group of patients. The patients with pSS and SSc are characterized by a steady progression of pSS with a slow and mild course of SSc throughout the observation period. The development of severe stomatological manifestations and high immunological activity of pSS contribute to the development of localized MALT lymphomas (70%) and disseminated MALT lymphomas (30%) with primary lesions of the salivary glands and transformation into DLBCL in case of their late diagnosis. The optimal method for preventing the development of NHL in this group of patients is the early diagnosis of pSS, the appointment of alkylating cytotoxic agents and/or anti-B-cell therapy in the early stages of pSS. Given the possibility of transformation of localized NHL into DLBCL, for early diagnosis, minimally invasive surgical biopsies of significantly enlarged parotid salivary glands should be performed before glucocorticoids are prescribed. Detection of positive B-cell clonality and lymphoepithelial lesions in the parotid salivary gland is considered a predictor of MALT lymphoma development during follow-up. Localized and disseminated MALT lymphomas in patients with pSS and SSc respond well to therapy, in contrast to MALT lymphomas transformed into DLBCL.

Установлено, что полиморфизмы генов медиаторов воспаления, тканевых матричных белков и ростовых факторов вовлечены в аутоиммунные и фибротические процессы при системной склеродермии (ССД). Хемокин CCL2 является ключевым воспалительным белком, присутствующим в циркулирующей крови и в очагах повреждения кожи больных ССД. Цель настоящего исследования состояла в изучении связи полиморфизма -2518 A/G гена CCL2 с уровнем С-реактивного белка (СРБ) у больных с разными клиническими и серологическими фенотипами ССД. В общей группе пациентов носители генотипа -2518АА имели статистически значимо более высокий средний уровень СРБ по сравнению с носителями аллеля -2518G (AG+GG генотипы) (р=0,032). Сходные различия уровней СРБ были получены у пациентов с диффузной формой ССД и у пациентов с позитивными титрами антител к топоизомеразе I (р=0,041 и р=0,042 соответственно). Выводы. Носительство генотипа -2518AА ассоциировано с высоким уровнем СРБ у больных с плохим прогнозом ССД (диффузная форма и позитивные титры аутоантител к топоизомеразе I) по сравнению с носительством аллеля -2518G. Полиморфизм -2518A/G гена CCL2 может быть использован в качестве генетического маркера тяжести и неблагоприятного прогноза ССД. It has been established that polymorphisms of inflammatory mediator genes, tissue matrix proteins and growth factors are involved in autoimmune and fibrotic processes in systemic scleroderma (SSc). CCL2 chemokine is a key inflammatory protein present in the circulating blood and in the lesions of the skin of patients with SSc. The purpose of this study was to study the association of the polymorphism -2518 A / G of the CCL2 gene with C-reactive protein (CRP) levels among patients with different clinical and serological phenotypes of SJS. In the general group of patients, carriers of the genotype -2518AA had a statistically significant higher average CRP level compared to carriers of the -2518G allele (AG + GG genotypes) (p = 0.032). Similar differences in CRP levels were obtained in patients with a diffuse form of SJS and in patients with positive antibody titers to topoisomerase I (p = 0.041 and p = 0.042, respectively). Conclusions: The carriage of the -2518AA genotype was significantly associated with a high level of CRP in patients with poor prognosis of SSc (presence of a diffuse form and seropositive autoantibody titers to topoisomerase I) compared with patients carrying the -2518G allele. Polymorphism -2518A / G of the CCL2 gene can be used as a genetic marker of severity and poor prognosis for SSc.

The aim of this study was to compare three semi-quantification scales for prospective assessment of scleroderma-associated interstitial lung disease (SS-ILD) severity. Methods. From 110 prospectively followed patients with SS-ILD, we selected 12 patients (mean age, 42 ± 13 years, 11 females) with obvious improvement (n = 6) or worsening (n = 6) of lung lesions on high resolution computed tomography (HRCT) during a year. The patients had diffuse (n = 7) or limited (n = 7) SS with mean length of the disease of 8.5 ± 6.7 years (range, 1 to 23 years). HRCT was done at baseline (inclusion in the study) and in a year. CT scans were quantitatively assessed by four radiologists including one experienced radiologist. A blinded analysis of HRCT scans was done using three scales: J.H.Warrick et al. (1991), A.U.Wells et al. (1997), and E.A.Kazerooni et al. (1997). The intraclass correlation coefficient (ICC) was calculated to evaluate the assessment reliability. T-test for independent samples was used to evaluate reproducibility of the assessments. Agreement between independent experts' opinions was evaluated using Kendall's rank correlation coefficient. Results. The measurements were significantly divergent between the radiologists, both for the baseline and the follow-up HRCT scans. ICCs for investigated radiological parameters were 0.56 to 0.76. The highest ICC (0.76) was obtained for A.U.Wells' scale. All scales used to assess HRCT scans had lower interoperator reproducibility. Conclusion. Combined use of currently available semi-quantification methods for follow-up assessment of HRCT in SS-ILD patients allowed thorough qualitative evaluation of lung lesions, but the reliability of the radiological parameters in detecting 1-year fibrosis progression in SS patients was low. The risk of significant interoperator bias limited the use of the radiological parameters in clinical trials of SS-ILD patients.

The objective of this 5year prospective study was to investigate a clinical role of isolated decrease of DLCO in patients with systemic sclerosis (SS) without pulmonary arterial hypertension (PAH).Methods. We selected 48 out of 142 patients with SS: 35 (73%) with limited SS and 13 (27%) with diffuse SS. The average length of the disease was 12.9 ± 7.9 years. Inclusion criteria were DLCO < 80% pred., forced vital capacity (FVC) ≥ 80% pred. and systolic pulmonary artery pressure (PAP) ≤ 35 mm Hg according to echocardiographic examination (echoCG). High resolution computed tomography (HRCT), spirometry, DLCO measurement, and echoCG were obtained at baseline and after 4.7 ± 1 year of follow up. All patients were treated with standard therapy.Results. CT signs of interstitial lung disease (ILD) were found in 43 (89.6%) patients at baseline and newly developed in 3 other patients during the followup. During the followup, lung CT improved in 5 (10.4%) patients and progressed in 15 (31.3%) patients. Over 5 years, FVC did not change significantly (97.6 ± 10.7% and 100.8 ± 18.9%; р = 0.15), while DLCO significantly decreased both in limited and diffuse SS groups (59.8 ± 13.5% and 56.3 ± 12%; р = 0.006). Mean PAP values remained within normal range in majority of patients. Clinically significant FVC reduction (≥ 10%) was found in 5 patients; of them, CT signs of ILD at baseline were seen in 3 patients and newly developed during the followup in 2 others. Clinically significant DLCO reduction (≥ 10%) was documented in 11 (23%) patients, all had CT signs of ILD at baseline, although CT progression during the followup was noted only in six of them. Contemporary deterioration in FVC, DLCO and CT was found in 3 patients.Conclusion. Clinical course of ILD in SS patients with isolated DLCO reduction and without PAH was relatively benign, with respiratory volumes being preserved within normal range for long time. Comparison of radiological and functional changes in a prospective study has suggested that DLCO is a more sensitive tool to determine ILD progression compared to HRCT. Regular DLCO measurements could be used as a reliable tool for monitoring of ILD associated with SS.

Aim: To assess prevalence of certain cardiac arrhythmias and conduction disturbances in the Russian population of systemic sclerosis patients using standard 12-lead and 24-hour electrocardiography (ECG); to estimate correlation between cardiac arrhythmia and clinical features of systemic sclerosis. Materials and methods: 80 systemic sclerosis patients and 60 sex- and age-matched controls were included. All patients underwent standard 12-lead and 24-hour ECG. Results: Arrhythmias on standard 12-lead ECG were demonstrated in 14 patients (17.5%) including sinus arrhythmia in 2 cases and premature beats in 13 cases (16%). Supraventricular (SV) and ventricular (V) ectopic beats were recorded in 5 (6%) and 7 (9%) patients, respectively; in one patient both SV and V ectopic beats were found. ECG signs of focal fibrosis were demonstrated in 9 patients (11%). In 24-hour ECG, frequencies of SV and V ectopic beats were 40 and 65%, respectively. Compared to the controls, systemic sclerosis patients had significantly higher prevalence and severity of cardiac arrhythmia. 36% of patients had high grade ventricular premature beats, associated with potential risk of life-threatening arrhythmia and sudden cardiac death. Conclusion: Cardiac arrhythmias and conduction disturbances are found in the majority of patients with systemic sclerosis. Standard ECG does not reflect true prevalence of cardiac arrhythmia in systemic sclerosis. In systemic sclerosis patients, 24-hour ECG is recommended as obligate method for initial examination and treatment efficacy control.

The new kit of reagents in format of the immunochip "ImmunoChip Borreliosis" for multiplex serologic analysis of mite-borne borreliosis demonstrated high diagnostic sensitivity and specificity. The percentage of detection of specific immunoglobulins was higher in "ImmunoChip Borreliosis" as compared with screening results in immune enzyme analysis. The high correlation between results of testing in immunochip and data of immune blotting is demonstrated to.

Objective: to estimate the detection rate of interstitial lung injury (ILI) and to characterize its manifestations from high-resolution computed tomography (HRCT) data in patients with systemic scleroderma (SSD). Subjects and methods. One hundred and thirty-eight patients with SSD (mean age 47±13 years, median disease duration (from the onset of the first signs but for Raynaud's phenomenon) 6 (range 2.5-11) years; mean systolic pulmonary artery pressure 25 (range 25-32) mm Hg) were examined. Chest HRCT was performed on a Siemens Somatom Emotion 6 apparatus. Results. ILI was found in 82% of the patients with SSD. The detection rate for ILI did not depend on the duration of SSD and was high just in the first years of the disease. The patients with lung injury at the onset of SSD were significantly older than those without lung injury (39 and 31 years, respectively; p < 0.03); and the rate of lung fibrous changes was higher in the older subjects who had the same duration of SSD. Lung parenchymal damage was symmetrical and characterized by the high detection rates of linear and reticular changes (100%), frosted glass symptom (64%), bronchiectases (58%), and signs of honeycomb lung (33%). There was a strictly sequential spread of CT changes from the basal segments of the lower lobes to segment VI and then to the overlying portions. When ILL afflicted the overlying portions, there was an increase in the frequency of the symptoms of irreversible fibrosis. Conclusion. Chest HRCT reveals the characteristic symptoms of ILI and reflects different phases of a fibrosing process in the lung. It is essential to make an in-depth examination using HRCT in all patients with SDD, irrespective of its clinical form in the earliest periods for the timely detection and treatment of ILI.

Objective: to study the time course of changes in serological inflammatory markers in patients with systemic scleroderma (SSD) on long-term statin treatment. Subjects and methods. The study covered 40 patients with SSD who were divided into a study group (n = 22) and a control one (n = 18). In the study group, in addition to the therapy performed atorvastatin was given in a dose of 10 mg/day in the first 6 months, 40 mg/day in 12 patients and in the former dose in 10 patients in the following 6 months. Enzyme immunoassay was used to measure the serum level of high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL) 6 in the study group at baseline and after 3, 6, 9, and 12 months of a follow-up and in the control group at baseline and after 12 months. Results. In the study group, the content of hs-CRP was 5.54±4.41 ng/l and increased in 13 (59%) patients. After 3, 6, 9, and 12 months, the level of hs-CRP was 3.93±3.13, 2.95±2.27, 3.15±3.01, and 2.86±2.27 mg/l, respectively, and was significantly lower than the base-line value (p = 0.002). In the same periods, the concentration of hs-CRP decreased by 25, 37, 35, and 35% of the baseline level and remained higher in 10 (45%), 10 (45%), 9 (41%), and 6 (27%) patients, respectively. The level of IL-6 was elevated in 10 of the 14 patients and exceeded in healthy donors. Following 12 months, it decreased from 6.61±6.37 to 1.89±2.71 pg/ml (p = 0.038), and the rate of its increment reduced from 71 to 14% (p = 0.007). In the control group, the levels of hs-CRP and IL-6 as the rate of their increment after 12 months, did not differ from the baseline values. In this group, the changes in the content of hs-CRP and IL-6 in that period were -0.42±2.32 mg/l and 0.14±4.15 ng/ml, respectively, and significantly less marked than those in the study group (p = 0.036 and p = 0.03, respectively). Conclusion. When long used, atorvastatin shows a stable anti-inflammatory effect in most patients with SSD.

Autoimmune reactions are of primary importance in the development of extrahepatic manifestations of viral hepatitis, among which there are rheumatic symptoms and syndromes. The incidence of clinically significant extrahepatic manifestations is shown to be relatively low, but they may be in the foreground in the clinical picture of the disease and are noted for severity. It is concluded that due to the high prevalence of hepatitis and the systemic pattern of their chronic forms, patients with extrahepatic manifestations of viral hepatitis may be encountered in the practice of a therapist and a rheumatologist. The onset of the infection caused by hepatitis viruses may be accompanied by articular lesion therefore the rheumatologist may be the first physician such a patient may resort to.

The study is aimed to investigate the process of endothelial repair related to endothelial progenitor cells (EPC) in systemic sclerosis (SS), and analyze the role of EPC abnormalities in endothelial dysfunction and impaired angiogenesis. Correlation between EPC circulating levels, measured by flowcytometry, and peripheral vascular manifestations, cardiac involvement, carotid artery disease, Framingham risk factor score, endothelial function and morphological signs of microangiopathy is explored. Our data demonstrate, that EPC reduction with disease progression is closely linked with endothelial dysfunction and destructive microangiopathy, and significantly contribute into development of severe cardiac disease and pulmonary hypertension in SS patients.

Objective. To determine diagnostic and prognostic significance of high-sensitivity Creactive protein (hsCRP) in systemic sclerosis (SS), to define relationship of this factor with activity of the disease and cardiovascular pathology, to assess role of pro-inflammatory cytokines in induction of acute phase proteins synthesis in SS. Material and methods. Serum levels of hsCRP, interleukin (IL) 6, IL 1β, IL1ra, IL 10, sIL2r were evaluated by enzyme immunoassay (EIA) in 40 pts with SS and 24 subjects of control group. Relationship with clinical features of the disease, endothelial dysfunction, capillaries structure changes, sub-clinical atherosclerosis, total coronary risk and some traditional cardiovascular risk factors was analyzed. Instrumental assessment included nailfold capillaroscopy, sonographic duplex examination of carotids , brachial arte ry sonographic examination. HsCRP prognostic significance was assessed in 51 pts with SS. Results. Elevated levels of hsCRP were found in 32% of SS pts and correlated with activity and severity of the disease, HAQ and SHAQ. Direct correlation of hsCRP with skin fibrosis distribution, interstitial lung disease, arthritis, laboratory indices of SS activity (ESR, sIL2r) and Scl-70 was revealed. HsCRP concentration in SS did not depend on character and intensity of cardiovascular pathology, subclinical atherosclerosis, endothelial dysfunction and proinflammatory cytokines production. Conclusion. HsCRP in SS reflects intensity of immuno-inflammatory process, correlates with T-cell activation markers and can be used as index of the disease activity, severity of skin and lung fibrosis.

Four foreign and one Russian 1st generation test-systems for detecting class G antibodies or summary antibodies to Borrelia burkdorferi sensu lato were comparitively investigated with the use of the clinical material under conditions of an encoded experiment. Cross reactions with sera from patients with syphilis, Epstein-Barr infection, cytomegalovirus infection and systemic lupus erythematosus were observed. The best specificity and sensitivity parameters were provided by the Enzygnost Borreliosis test-system.

One foreign and two Russian recombinant enzyme immunoassay test-systems were comparatively investigated under conditions of an encoded experiment. Sensitivity in the experiment with the Russian test-systems Borreliosis-ELISA-IgG and Lyme Best was 63.8 and 68.8% respectively. As for the test-system Borrelia IgG Recombinant, it was 47.5%. All the test-systems were highly specific (94.4 to 99.5%). The test-systems Lyme Best and Borrelia IgG Recombinant revealed partial cross reactions with sera from patients with systemic lupus erythematosus and leptospirosis.